Running Head: PEDIATRIC DEVELOPMENTAL PAPER

Pediatric Developmental Paper

Arlena Davis

Subjective

Clarissa is a 3 year old girl with upper respiratory infection. She has always lived with her parents and, grandmother in the same place. Her parents are mainly responsible for raising her since she was born. However, the child spends most of the time with her grandmother as the parents go to work. The caregiver described the child as calm, playful, hot tempered and shy. The grandmother spends more than 8 hours with the child as her parents go to work at 8.00am and come back at 5.00pm. The child wakes up at 8. 00 am and eats her meals with the grandmother. However, the child interacts with her parents during dinner and bedtime. The caregiver and the child interact well as the toddler shows affection by hugging. However, the caregiver identified the child’s upsetting behaviors including pushing people when she is angry. The caregiver disciplines the child when she misbehaved or went to dangerous places (Burns et al., 2013).

Additionally, the parents worry about the child’s safety at home since she likes going to dangerous places. The grandmother finds it challenging to control the child’s movement since she is starting to learn about her surroundings. The parents also do not get adequate support from family members as they only rely on the child’s grandmother. However, they count on few friends for help since they have a large social network (Burns et al., 2013). The parents and the grandmother do not spend adequate time with friends, and thus the small social circle. The father is involved in the care giving role according to the grandmother and the mother. The father is helpful as he assists in feeding the child and playing with her. In addition, the mother did not have complications during pregnancy and the baby was not born premature. The baby was almost 3.2 kgs and 19 inches at birth. The parents take the child for healthcare at different facilities including emergency rooms and walk-in clinics (Burns et al., 2013).

The child has normal growth, appetite, bowel movement, urination and sleep patterns. However, the caregiver claims the child got sick often and she has to call her parents to take her to the hospital. Despite the sickness, the child has managed to learn new words and sounds. The child does not have visual and hearing (Burns et al., 2008). The child interacts well with other people, but the caregiver is worried about the Childs frequent sickness. The family has no major issues and concerns as there is one ill, alcoholic, using drugs or behaving strangely (Provence & Apfel, 2001). The family has satisfactory housing and lives in a safe neighborhood. The family does not deal with fear of violence and no one owns a gun. Nonetheless, the family has financial problems and found it challenging to meet basic needs like paying rent and bills.

Observation

The child has had normal gross and motor development from 6 months up to now according to the caregiver (Provence & Apfel, 2001). The child was able to sit alone, stand and grasp objects with the index and thumb finger according to the caregiver by 12 months. She could walk independently and scribble with crayon on paper. Additionally, she could build powers of cubes by the age of 18 months and squat and stand at 21 months. Also, she could jump off floor with two feet. She can hold crayon with thumb and finger and duplicate cross on the paper. The child has also had a normal social and emotional development as reported by the caregiver. The child was able to differentiate the main caregiver from other people and establish social contact by smiling by 6 months. She also played social games and enjoyed playing with dolls. She also showed affection to the caregiver and helped her with house chores and organizing things. Nevertheless, she expressed differ emotions including anger, anxiety and sadness by 12 months. She also found it challenging to cooperate while playing with other children. The child has no language development problems as she can speak and answer comprehension questions well. She has coping and self- development issues (Provence & Apfel, 2001). She pushes away unwanted people, diet and objects. On the other hand, she can feed self with a spoon and drink from the cup without assistance. She also helps with dressing. Therefore, the child’s gross and fine motor development, language development and coping and self-help development are at age level. The child’s social and emotional development is below age level.

Assessment

Clarissa has a normal development in different areas including language, fine and gross motor, coping and self- help development (Provence & Apfel, 2001). However, she has an abnormal social and emotional development. She is unable to manage her emotions when playing with other children, with the caregiver and other people. She expresses negative emotions including anger and sadness. She pushes away people, objects and foods she does not like. The caregiver and the child interact well as she shows affection to the caregiver by hugging. The child has a positive relationship with the family members including mother and father. Nonetheless, the frequent sickness may affect the child’s development as she has upper respiratory infection (Provence & Apfel, 2001). The family seeks medical care from the emergency room or walk-in clinics when the child is sick. However, the family concerns include inadequate finances to meet basic needs and safety of the child at home. The child spends most of the time with the grandmother and she is unable to control and prevent the child from going to dangerous places. The family members have a small social network as they do not spend sufficient time with friends. They get financial and social support from the grandmother and few friends. The family has no history of alcoholism or fear of violence.

Plan

The following interventions will be implemented to address the concerns and issues raised by the caregiver and parents. Improving the safety at home is critical to prevent accidents. In this case, parents and the grandmother will be educated on the importance of safety at home to improve the child’s wellbeing. Dangerous substances including poisonous liquids should be stored far from the child to decrease accidents (Burns et al., 2008). The home should be redesigned to eliminate dangerous places and hence promote the child’s safety. Adaptations including fireguards and stair gates make the home safe. Further, providing medical care to the child is important to improve her health outcome and quality of life. Different medications will be administered to treat upper respiratory infections including Tylenol, Motrin, Benadryl and cough drugs. Additionally, social support interventions will be provided to improve the social wellbeing of the family. Social support interventions are important in increasing social networks or circles and enhancing physical and mental wellbeing (Burns et al., 2013). The parents and the grandmother will be able to share their concerns with friends and get necessary support. Lastly, the child should socialize with caregiver, peers and other adults to develop social and emotional skills. Adults should respond to the child’s signals in a reliable and predictable manner to enable her regulate emotions (Burns et al., 2013).

Reference

Burns, C. E., Dunn, A. M., Brady, M. A., Barber Starr, N., & Blosser, C. G. (2013).

Pediatric primary care.

(5th ed.). Philadelphia, PA: Elsevier Saunders.

Burns, C. E., Dunn, A.M., Brady, M.A., Starr, N. B., & Blosser, C.G. (2008).

Pediatric Primary Care-pageburst on vital source.

Saunders: Elsevier Health Sciences

Provence, S., & Apfel, N. H. (2001).

Infant-Toddler and Family Instrument

. Baltimore, MD: Brookes Publishing

Overview

According to the National Aboriginal Health Organisation (NAHO, 2003), the term ‘traditional’ was introduced by the British during the colonial era and often rejected by many indigenous peoples. Authorities in the industrialised world used the term ‘traditional medicine’ to distinguish between Western medicine and medical knowledge and practices that were local to indigenous tribes in Africa, South East Asia and other parts of the third world. Today traditional medicine is also referred to as Complementary and Alternative Medicine (CAM) (Shaikh & Hatcher, 2005). Chronic social, economic and political problems in many third world countries means that the vast majority of their populations have little or no access to modern medical resources. By contrast, traditional medicine is often available to the masses and may constitute the only available health care resource. This essay discusses the role of traditional medicine as an essential resource in the third world, with specific reference to Nigeria and Pakistan.

Traditional Medicine

There is no universally accepted and unambiguous definition of traditional medicine, largely because of differences in culture, language, and medical products and practices across the third world. However, the World Health Organisation defines traditional medicine as “health practices, approaches, knowledge and beliefs incorporating plant, animal and mineral based medicines, spiritual therapies, manual techniques and exercises, applied singularly or in combination to treat, diagnose and prevent illnesses or maintain well-being” (WHO, 2003). Traditional medicine generally refers to any medicinal knowledge and practices that aren’t within the domain of modern day Western medicine. Like modern medicine the ultimate goal of the traditional healer is to improve the well being of individuals who present with some undesirable physical or psychological malady (Shaikh & Hatcher, 2005). However, traditional medicine is unique in that improvements in well-being may incorporate spiritual healing, and whereas western medicine largely relies on science-based knowledge and procedures, traditional medicine is based on local rituals, herbs, and superstitions indigenous to the local community (NAHO, 2003).

Traditional medicine may incorporate different fields of expertise. NAHO (2003) identifies several types of specialists, including the spiritualist, herbalist, medicine man/woman, and healer. Spiritualists specialise in spiritual healing, for example by communicating with dead ancestors and performing ritualised sacrifices (e.g. killing a chicken). They often enjoy a certain degree of authority within local communities, serving as mentors for individuals or families. Herbalists are perhaps equivalent to pharmacists and pharmacologists in western medicine. They are experts on the medicinal properties of local plants and are typically called upon to prepare various medicinal concoctions to cure specific ailments. Such preparations may be in the form of a meal, drink, or even special soap for bathing. Healers are individuals with a natural talent for healing, often through spiritual or other means, perhaps similar to the ‘psychic’ in Western society. Indeed, there seems to be a high degree of overlap between healers, and spiritualists, albeit this is debatable and culture-specific. Finally, the medicine man/woman is a traditional healer usually involved in ceremonial activity, such as a funeral. They often carry a lot of material effects, such as mysterious ‘bundles’, bones, and other effects. Chronic shortages of modern health care resources in the third world has led to renewed interest in the role that CAM could play in reducing premature morbidity and mortality.

Health care in the third word

Populations living in third world countries are plagued by a variety of health problems. These include childbirth problems such as low birth weight (Arif & Arif, 1999), nutritional problems, notably malnutrition, hypoglycaemia and hypothermia (Bhan et al, 2003), kidney disease (SantaCruz, 2003), degenerative psychiatric illnesses such as Hodgkin’s disease (Hu et al, 1988), hypertension (Galie & Rubin, 2004), tobacco-related illness (Tomlinson, 1997), and so on. The prevailing economic, political, social and environmental conditions aren’t ideal for maintaining good health (Cooper, 1984). Socio-economic inequalities caused by flawed economic policies and political corruption has meant that modern medicine is beyond the reach of the suffering masses. Environmental decadence manifests in poor sanitary conditions, itself a result (at least in part) of weak economic infrastructure, and political leadership. Governments in many third world countries often spend only a fraction of their gross domestic product (GDP) on health care, so that there is a chronic shortage of both primary and secondary health resources such as clinics, hospitals, staff, and drugs. Health care policies are either absent, inadequate or poorly implemented. Lack of adequate funding stifles research and development, not withstanding positive side effects like increased creativity (Coloma & Harris, 2004).

These deplorable conditions have persisted despite massive financial investment by the World Bank. The organisation pays out an estimated $28 billion annually to third world countries, some of which is meant be used for the development of adequate health infrastructure (Pinker, 2000). But this has had little effect, partly because of government corruption, political instability, and crippling national debts. Moreover, technological change is so rapid that investment in essential medical equipment is not viable, unless there is a regular cash flow to finance replacements (Coloma & Harris, 2004). Much has been written about the problem of ‘brain drain’ in which locally trained professionals flee their under-resourced and decaying health care systems to take up more lucrative jobs abroad (Fisher, 2003; Latif, 2003; Levy, 2003). Then there is the capitalist constraint. Private companies in the West that provide health services, pharmaceuticals, equipment, and other medical resources need to make a profit to stay in business. This means selling products to their clients (governments, health service organisations, the general public) at a cost-effective price, which third world countries simply cannot afford. Getting private companies to sell their health services and products at a loss, for example by provide cheap or free drugs, often requires government intervention and corporate will (Enserink, 2000), both of which are often lacking. In the midst of such adversity traditional medicine may provide the only viable source of health care.

Nigeria

Modern health care in Nigeria incorporates primary care provided by local government and privately owned clinics, secondary care dispensed by hospitals, and tertiary services (e.g. orthopaedics, psychiatry) provided by specialist hospitals (WHO, 2002-2007). Like many third world countries the health infrastructure is severely under funded, with chronic equipment and staff shortages (Kadiri, 2005). Brain drain is a constant problem (Levy, 2003), and adequate health care is expensive and hence beyond the reach of the masses (WHO, 2002-2007). Traditional medicine operates side-by-side with modern health care. Most Nigerians have access to traditional healers, or ‘medicine men’, especially in the rural areas where people lack local health infrastructure and transportation to travel to the nearest clinic or hospital. Thus, CAM is the only health resource available to most Nigerians (Mpyet et al, 2005). Nigeria is actually a ‘melting’ pot of over 300 different tribes


^[1]

, with remarkably different languages, cultures, lifestyles, religions and traditional governments (at local level). Thus, the practice of traditional medicine is quite varied across the country. Nevertheless, most medicine men are considered ‘experts’ in the preparation and administration of various herbal medicines, and the prognosis for patients is often good. The use of herbal drugs remains very popular, especially amongst the older generation and/or less educated.

Recent evidence suggests that some Nigerians are suspicious of modern medical procedures and consequently fail to utilise services to which they have access. Raufu (2002) and Pincock (2004) both document a recent health crises in northern Nigeria in which parents refused to get their kids vaccinated against poliomyelitis. There was considerable scepticism about the vaccination campaign, with many parents fearing their children may become infected with the HIV, or worse become infertile, irrespective of what the health officials said. This incident seems to mirror a subtle nation-wide cultural shift towards traditional medicine. For example, there have been calls for traditional healers to be involved in making referrals to secondary care services, along side professional medical doctors (Mpyet et al, 2005). The WHO has specifically encouraged research on traditional medicine in Nigeria, and the National Institute for Pharmaceutical Research and Development (NIPRD), located in Abuja, the capital city, has been identified as a possible location for such research. The NIPRD was set up to conduct research projects designed to improve, refine, and modernise traditional medicine, especially in terms of herbal remedies. The institute has successfully developed some herbal medicines including NIPRD AM-1, a herbal extract for treating malaria.

In other parts of the country steps have been taken to ‘blend’ traditional medicine with modern medical procedures. The Fantsuam Foundation (IHDC, 2003), a women’s group founded in 1996 and based in northern Nigeria with over 80,000 members, was set up to help rural women fight their way out of poverty. This organisation is not profit oriented, works in collaboration with local government, and uses modern computer resources, such as electronic commerce. The foundation recognises the value of CAM especially amongst women living in poor communities, and works to reconcile traditional practices with modern medicine. Women in this part of the country are plagued by a variety of health problems ranging from minor ailments (e.g. back pains) to more serious conditions (e.g. HIV/AIDS). Thus, there is an ever-present demand for appropriate health care. Traditional healers are very active, using various emollients and herbs to treat patients. More encouragingly, the Foundations’ work in the community has highlighted several interesting points concerning the modernisation of traditional medicine. These include the following; Some aspects of traditional medicine can be improved for better health service provision; Traditional healers are open to modernisation initiatives provided there is a sense of partnership and intellectual property rights are protected; Traditional medicine as a body of knowledge can be preserved while simultaneously opening it up to reforms. Overall, the value of traditional medicine as a widely available health resource is universally recognised in Nigeria.

Pakistan

Pakistan like other third world countries suffers from an under funded and under-resourced modern health care system. Poverty-related health problems are rife, including low birth weight (Bhutta et al, 2004), hepatitis (Yusufzai, 2004), sexually transmitted diseases (Wallerstein, 1998) and high infant mortality and malnutrition (Abbasi, 1999). The health care system is dichotomised into the public and private sectors. The former incorporates a mixture of mostly unregulated private hospitals, clinics, and traditional healers, while the public sector is made up of government run hospitals, mostly in very poor condition (Shaikh & Hatcher, 2005). Overall, Pakistan’s health service system does not compare favourably with its neighbours. Poverty, illiteracy and poor sanitation, as well as political instability compound the problem, with infant mortality and infectious disease particularly problematic (Abbasi, 1999; Zaidi et al, 2004). Historically CAM has been a permanent part of the health care landscape in Pakistan, practised in the form of ‘Unani’, ‘Ayurvedic’ and homeopathic systems (Shaikh & Hatcher, 2005). Unani medicine entails the use of natural resources normally found in the body, such as clean and fresh water, whereas Ayurveda remedies are sensitive to a woman’s natural rhythms and cycles.

There is particular emphasis in Pakistan on the use of plant-based traditional medicines, albeit animal based products are sometimes used. In the midst of chronic and widespread socio-economic deprivation more and more Pakistanis are turning to traditional healers for their health care (Shaikh & Hatcher, 2005). Local ‘hakeems’, religious leaders and medicine men regularly dispense traditional therapies. These individuals enjoy considerable public trust and respect, especially in the rural areas, and patients regularly present with a wide range of medical conditions including gynaecological problems. According to Jafry (1999) traditional medicine was officially acknowledged in Pakistan under the Unani, Ayurvedic and Homeopathic Practitioners’ Act of 1965. The practice of homeopathy in particular has become well established, with increases in the number of homeopathic (privately owned) schools, especially after the Homeopathic Board and National Council for Homeopathy (NCH) was set up. Currently there is an abundance of homeopathic clinics, pharmaceutical companies, and other related organisations in Pakistan. Interestingly, despite these advances Pakistan continues to import homeopathic medicines in large quantities and local drug prices remain high. Consequently many Pakistanis cannot afford homeopathic treatment. Like the modern health care system which is heavily under funded ((Abbasi, 1999), homeopathic medicine remains crippled by under investment (Jafry, 1999). Despite these drawbacks, CAM as a whole remains more accessible than modern health resources, and constitutes an indispensable resource for the vast majority of the population (Shaikh & Hatcher, 2005).

Exploitation

NAHO (2003) has identified a number of important concerns that need to be recognised if CAM is to be successfully integrated with modern medicine in developing nations. Firstly it is essential to recognise the important role played by the elderly, who form the bulk of spiritual healers and medicine men. Less common in Western culture, high reverence for elders in many third world countries is a major reason traditional medicine enjoys considerable public endorsement. Secondly, there is the risk of exploitation by unscrupulous western private enterprise. In particular it would be wholly inappropriate in a cash economy for a private pharmaceutical company, concerned about making a quick profit, to offer symbolic but worthless ‘gifts’ to a traditional healer in return for valuable knowledge on local medicines, ointments and herbs. Thirdly, there is the issue of intellectual property rights. These must be protected under any circumstances, again to avoid unfair exploitation and profiteering by private companies. Health care funding provided to third world governments by the WHO, World Bank, and other financial organisations should be conditional on the establishment and implementation of satisfactory protective policies. For example independent (e.g. WHO) officials can be used to supervise contracts that are drawn up between private enterprises and traditional healer groups.

Conclusions

As early as 1984 Cooper argued that Western medicine might not really be suitable for the third world (Cooper, 1984). Despite the rapid spread of modern medicine CAM remains an indispensable resource for providing adequate health care to the majority of individuals living in these countries. Socio-economic and political problems have severely limited access to modern health care. However, considerable progress has being made towards harness the potential of traditional medicine, for example by allowing traditional healers to make hospital referrals. Both the WHO and World Bank seem committed to promoting the development of CAM. Given the complexity and variability of health provision across the third world it may be necessary to tailor health care reform to the peculiar requirements of each country (Buch, 2005). Traditional medicine is firmly rooted in local culture and customs (NAHO, 2003), and therefore traditional health protocols cannot be generalised across nations. Additionally, concerns about equality, protection rights, and other ethical issues need to be addressed.

References

Abbasi, K. (1999) The World Bank and world health – Focus on South Asia II: India

and Pakistan

British Medical Journal

, 318, pp.1132-1135

Arif, M.A. & Arif, K. (1999) Low birthweight babies in the third world: maternal

nursing versus professional nursing care,

Journal of Tropical Paediatrics

, 45,

pp.278 – 280.

Bhan, M.K., Bhandari, N. & Bahl, R. (2003) Management of the severely

malnourished child: perspective from developing countries.

British Medical

Journal

, 326, pp.146 – 151

Bhutta, Z.A., Khan, I., Salat, S., Raza., F. & Ara, H. (2004) Reducing length of stay in

hospital for very low birthweight infants by involving mothers in a stepdown

unit: an experience from Karachi (Pakistan). British Medical Journal, 329,

pp.1151 – 1155

Buch, E. (2005) The future of health care in Africa.

British Medical Journal

. 331,

pp.1-2.

Coloma, J. & Harris, E. (2004) Innovative low cost technologies for biomedical

research and diagnosis in developing countries.

British Medical Journal

, 329,

pp.1160- 1162

Cooper, J.A.D. (1984) Health resources: the United States and the third world,

Health

Affairs

, 3, pp.149 – 151

Enserink, M. (2000) Group urges action on third world drugs.

Science

, 287, p.1571

Fisher, J.P. (2003) Third world brain drain: Brain drain must be halted.

British

Medical Journal

. 327, p.930.

Galie, N. & Rubin, L.J. (2004) Introduction: new insights into a challenging disease:

A review of the third world symposium on pulmonary arterial hypertension.

Journal of American College of Cardiology

, 43 (12 Suppl S): 1S.

Jafry, S.A.A. (1999) Homeopathy in Pakistan [online]. The Homeo Webzine.

Available from:

<

http://www.geocities.com/pulsnet2000/homeopak.htm>

[Accessed 5 March

2006].

Kadiri, S. (2005) Tackling cardiovascular disease in Africa.

British Medical Journal

,

331, pp.711-712.

Hu, E., Hufford, S., Lukes, R., Bernstein-Singer, M., Sobel, G., Gill, P., Pinter-

Brown, L., Rarick, M., Rosen, P. & Brynes, R. (1988) Third-World Hodgkin’s

disease at Los Angeles County-University of Southern California Medical Center

Journal of Clinical Oncology

, 6, pp.1285 – 1292.

IHDC (2003)

Local health content in Nigeria blends tradition and science

.

Johannesburg: IHDC.

Latif, A.S. (2003) Third world brain drain: Causes of exodus need to be examined and

rectified.

British Medical Journal

, 327, p.930.

Levy, L.F. (2003) The first world’s role in the third world brain drain.

British Medical

Journal

, 327, p.170

Mpyet, C, Dineen, B.P., & Solomon, A.W. (2005) Cataract surgical coverage and

barriers to uptake of cataract surgery in leprosy villages of north eastern

Nigeria.

British Journal of Ophthalmology

, 89, pp.936-938.

NAHO (2003)

Traditional Medicine in Contemporary Context: Protecting and

Respecting Indigenous Knowledge and Medicine

. Ottawa, ON: NAHO.

Pincock, S. (2004) Poliovirus spreads beyond Nigeria after vaccine uptake drops.

British Medical Journal. 328, p.310

Pinker, S. (2000) Banking on the Third World.

Canadian Medical Association

Journal

, 163, p.94

Raufu, A. (2002) Polio cases rise in Nigeria as vaccine is shunned for fear of AIDS

British Medical Journal

, 324, p.1414.

SantaCruz, P.L. (2003) Preventing end-stage kidney disease: a personal opinion from

the Third World.

Nephrology Dialysis Transplantation

, 18, p.2453.

Shaikh, B.T. & Hatcher, J. (2005) Complementary and Alternative Medicine in

Pakistan: Prospects and Limitations.

Evidence-Based Complementary and

Alternative Medicine

, 2, pp.139–142.

Tomlinson, R. (1997) Smoking death toll shifts to third world

British Medical

Journal

, 315, pp.563 – 568

Wallerstein, C. (1998) Pakistan lags behind in reproductive health.

British Medical

Journal

. 317, p.1546

WHO (2003)

Country Press Releases: WHO encourages Research into Traditional

Medicine

. Geneva: WHO.

WHO (2002-2007)

WHO Country Cooperation Strategy: Federal Republic of Nigeria.

Geneva. WHO

Zaidi, K.M., Awasthi, S. & deSilva, H.J. (2004) Burden of infectious diseases in

South Asia.

British Medical Journal

, 328, pp.811 – 815.

Yusufzai, A (2004) Pakistan medical association warns of potential rise in hepatitis

British Medical Journal

. 329, p.530.

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Footnotes

^[1]
There are three major tribes; The Hausa, Ibo, and Yoruba.

The immune system is of great importance for protection of the organism against foreign substances, and consists of molecules, cells and tissues that work collectively to provide this protection. One of the key members of the immune system is the MHC (Major Histocompatibility Complex), a molecule expressed on antigen presenting cells, such as macrophages, dendritic cells and B cells, and required for the proper antigen presentation. The MHC is responsible for binding peptides originated from foreign proteins and displaying them on the surface of antigen presenting cells, allowing their recognition by T cells, which will initiate an immune response. MHC molecules are highly polygenic, which means that there are multiple different MHC genes, and consequently different sets of MHC molecules with different specificities in each person. Besides that, MHC genes are also very polymorphic, with many different variants in the population.

^1-3

The human MHC genomic region, on chromosome 6, encodes HLA (Human Leukocyte Antigen) genes, and the great diversity previously cited is responsible for the differences seen in immune responses within a population.

^1,4

There are two main classes of HLA (I and II), both responsible to present peptides to T cells and trigger an appropriate immune response. The main difference between these classes is that HLA I molecules present endogenous antigens derived from viruses and phagocytosed or internalized pathogens to CD8+ T cells, triggering a citolytic response on recognized cells, while HLA II molecules present exogenous antigens generated intracellularly in antigen presenting cells to CD4+ T cells, that will trigger the production of antibodies by B cells.1,3,5 Besides that, HLA I and II are differently expressed on cells: HLA class I is expressed in almost all cells of the body, in high frequency on cells of the immune system and in low frequencies in non-nucleated cells, while HLA class II is exclusively expressed on cells involved in immune responses, such as antigen presenting cells.1,2 Both HLA classes I and II are divided into subtypes, being A, B and C the three more important of HLA class I, and DR, DP and DQ the three more important in the case of HLA II.2,3 Besides that, in the region in between HLA I and II regions it is possible to find HLA class III genes, that encodes some complement proteins such as C4A, C4B, C2, and factor B, some cytokines, such as TNF alpha and beta, and some other non-HLA proteins.2,4,6

The adaptive immune system should ensure that the organism do not respond to its own proteins, otherwise it will result in injury to itself. This feature is called self-tolerance, which means that in a normal individual, the immune system has tolerance to self-proteins, being able to do not trigger an immune response against them.1,4,7 This self-tolerance is maintained by two main steps: a) Thymic selection is a process that consists in presentation of self-proteins to T cells precursors in the thymus and elimination of the ones that present reactivity to them. During this step, approximately 95% of the T cells precursors are eliminated by apoptosis because of their reactivity. The surviving ones go out of the thymus as mature T cells, after passing through a process called positive selection.4,8 b) Since not all of the self-reactive T cells are eliminated in this first selection, mature T cells undergo a peripheral secondary selection in lymphoid and nonlymphoid organs, so the remaining self-reactive T cells can be eliminate. Besides that, there is a production of regulatory T cells during thymic selection and in the periphery, that are important to help in the peripheral control self-reactive T cells that were able to escape of elimination.4,7,8

When a breakdown in this self-tolerance occurs and the adaptive immune system reacts to self-proteins, a sustained immune response follows, because it is not possible to promote the clearance of this antigen from the organism. This process, which will lead to inflammatory tissue injury, is also known as Autoimmune Disease, and can have very different manifestations depending on its location.1,4,9,10 According to the review conducted by Gregersen and Behrens (2006)4, around 3% of the population have a known Autoimmune Disease, even though not recognized autoimmune mechanisms can influence other common disorders.

Some authors consider this breakdown or absence of tolerance questionable, as stated by Möller (1998).11 Among other things, even in a normal and healthy organism there are some possible autoreactive T cells circulating peripherally, and this disruption of self-tolerance was never proved in experiments. Still, thinking about self-tolerance as something limited only to the self-antigens that were presented on thymic selection, it remains uncertain if autoimmune responses arises from a self-tolerance disruption or from the potential threat of these normally existing autoreactive T cells.11

Although the exact aetiology of Autoimmune Diseases is not completely certain, there are some known factors related to them, such as environmental triggers (e.g. chemical agents and pathogens), hormonal influences (e.g. estrogen), and region and ethnic differences, but the most important determinant of Autoimmune Diseases is the genetic susceptibility, mainly associated with certain HLA alleles, because of their central action in immune responses.1,4,9,10

Any disturb on HLA expression can lead to development of an Autoimmune Disease because T cell precursors also require HLA to present self-antigens, and if HLA molecules cannot present self-antigens to autoreactive T cells, they will not be eliminated during thymic selection and will circulate in the organism.1,4,8 Besides that, another possible explanation to the influence of HLA on predisposition to Autoimmune Diseases is that self-antigens attached to certain HLA molecules are responsible for driving the positive selection of T cell precursors specific for them, depending on their level of expression: if they are present at small amounts or if they cannot bind properly to HLA molecules, they will conduct the negative selection, and if they are present at the degree needed or if they bind effectively they will conduct the positive selection. Then, insufficient expression of self-proteins during the thymic selection could increase the susceptibility for the development of an Autoimmune Disease. 1,4 There are some theories to explain the separate mechanisms by which HLA class I and II can influence the predisposition to Autoimmune Diseases, cited by Gough and Simmonds (2007).3 Concerning to HLA II mechanisms, in addition to this possibility of low affinity self-antigens leading to impaired elimination of self-reactive T cells, changes in the binding region of HLA II molecules could predispose mature T cells to recognize only a specific group of self-antigens, as a result of ineffective and incomplete thymic selection. Another discussed idea is that polymorphic regions of the receptor of HLA II molecules could lead to selection of ineffective regulatory T cells or self-reactive T cells, predisposing to Autoimmune Diseases.3 On the other hand, concerning to HLA I mechanisms, it is possible that the endogenous antigens presented, such as viruses and phagocytosed bacteria, predispose to an autoimmune response by mimicking self-antigens and activating autoreactive T cells.3,11 Besides this hypothesis, it is believed that some of these peptides can alter HLA I inhibitory activity on NK cells, which would act by lysing the cell and triggering a potential autoimmunity.3,13

Most of the known and described Autoimmune Diseases are related to an alteration of HLA II molecules, and some of the main examples include Rheumatoid Arthritis, Type 1 Diabetes and Hashimoto’s Thyroiditis. Ankylosing Spondylitis is another well-studied and important Autoimmune Disease, although it is associated with HLA I molecules.3,12

Rheumatoid Arthritis is one important example of cell mediated Autoimmune Disease, caused indirectly by T-lymphocytes and associated mainly with environmental factors and genetic susceptibility, among other potential influences. It is a chronic inflammatory disease that affects multiple synovial joints, such as fingers, knees, elbows, shoulders and ankles, with systemic psychological and systemic repercussions, affecting cardiovascular, respiratory, and skeletal systems.14 According to the review conducted by Ghodke et al (2005)10, it occurs worldwide in a prevalence that varies from 0.3 to 1.5% in almost all populations, being women more susceptible than men. In summation, the mechanism of the disease begins when a self-antigen, still uncertain, but probably a peptide derived from the connective tissue (e.g. collagen) is recognized by T cell receptors of CD4+ T cells, which release cytokines (e.g. IFN-). These cytokines promotes phagocyte activation and release of other cytokines, including TNF-ɑ, interleukins and other substances that along with IFN- will activate resident synovial cells to produce proteolytic enzymes (e.g. collagenase). As a result, there is inflammation on the synovial tissue (also known as synovitis), destruction of synovial cells and synovial hyperplasia, followed by cartilage damage and bone erosion and consequent destruction of the joints.1,14

Several genetic loci are associated with susceptibility to Rheumatoid Arthritis, but the most studied and well-known of them is the HLA class II DRB1,4,9,11,12,14 contributing to a third to half of the general genetic predisposition risk.15 The hypothesis first presented by Gregersen (1987)16, suggests that some HLA-DRB1 alleles express a “shared epitope”, that is a five amino acid sequence (QKRAA) responsible for the increased susceptibility to Rheumatoid Arthritis by influencing peptide binding and interaction between HLA and T cell receptor.15,17 These HLA-DBR1 alleles include DRB1*0101, DRB1*0102, DRB1*0401, DRB1*0404, DRB1*0405, DRB1*0408, DRB1*1001 and DRB1*1402.3,16 As summarized by McInnes and Schett (2011), the function of HLA-DRB1 in the pathogenesis of this disease is related to MHC molecule-based antigen presentation, self-antigen selection and T cell repertoire. However, they also present multiple other ideas as possibilities of influence of HLA-DRB1 on Rheumatoid Arthritis, including senescence induction on T cells and a potential proinflammatory function.14 The study carried out by de-Vries (2002) suggested another association between HLA-DRB1 and Rheumatoid Arthritis, but in a distinct way: differences in the regular shared epitope may have a protective effect, rather than a predisposing effect. These HLA-DRB1 alleles include DRB1*07, DRB1*1201, DRB1*1301 and DRB1*1501, among others.18 Besides HLA-DRB1, many other non-HLA genes were described as having a potential link with Rheumatoid Arthritis, such as PTPN22, AFF3, CD28, CD40 and CTLA4, among other ones.

The symptoms of Rheumatoid Arthritis include pain and stiffness of the affected joints, both usually in the morning or after resting, as well as warmth, redness and long-term deformities. The treatment may be performed in a multidisciplinary way, with physiotherapy, occupational therapy, diet, pharmacological treatment and complementary therapies. The pharmacological management may include symptom control with analgesics and NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), glucocorticoids, DMARDs (Disease Modifying Anti-Rheumatoid Drugs) and biological drugs, depending on each case.19

Type 1 Diabetes, also known as Insulin Dependent Diabetes Mellitus (IDDM), is a multi-systemic metabolic disease, originated as a result of impaired insulin production and/or function and associated with genetic predisposition and environmental factors. It is another important example of a cell mediated Autoimmune Disease where a self-antigen, such as insulin or other Islet of Langerhans proteins, activate CD4+ T cells triggering the release of cytokines by activated phagocytes and activation of in situ CD8+ T cells, leading to inflammation and injury of insulin-producing pancreatic β-cells.1,15,20 Because of reduction of insulin production, there is a disturbance in blood glucose control, leading to clinical symptoms caused by hyperglycaemia and ketoacidosis.

Several genetic loci were also described as being related to Type 1 Diabetes, but it is known that this disease has a particular link with HLA-DR3, DR4, DQ2 e DQ8, especially when combined DR4-DQ8 or DR3-DQ2.9,20 According to Devendra and Eisenbarth (2003), these two combination of HLA alleles are found in 9 out of 10 people with Type I Diabetes. As well as in Rheumatoid Arthritis, some protective HLA molecules were described, being DQA1*0102-DQB1*0602 the most common and effective of them, and several other non-HLA genetic loci have been described as potential influences on Type 1 Diabetes, but only one was proved to be associated: IDDM 2 on chromosome 11p5.5.21

As suggested by one of the names of the disease, injection of insulin is essential for regulation of blood glucose levels and for the effective treatment of Type 1 Diabetes. However, hypoglycaemia (low blood glucose levels) can occurs with treatment using insulin, mainly when used in excess, and because of this, another important part of the treatment is the monitoring of blood glucose levels.

References

1. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York:
   
   Garland Science
   
   2001.
   
   www.ncbi.nlm.nih.gov.ezproxy.liv.ac.uk/books/NBK10757/
   
   (accessed 27 Mar 2014)

2. Robinson J, Halliwell JA, McWilliam H, Lopez R, Parham P, Marsh SGE. The IMGT/HLA Database Nucleic Acids Research; 2013;41:D1222-7.
   
   www.ebi.ac.uk/ipd/imgt/hla/
   
   (accessed 27 Mar 2014)
3. Gough SCL, Simmonds MJ. The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. Paris: Curr Genomics 2007;8(7): 453–465.
   
   www.ncbi.nlm.nih.gov/pmc/articles/PMC2647156/
   
   (accessed 27 Mar 2014)
4. Gregersen PK, Behrens TW. Genetics of autoimmune diseases – disorders of immune homeostasis. Nature Reviews Genetics 2006;7:917-928.
   
   www.nature.com/nrg/journal/v7/n12/full/nrg1944.html
   
   (accessed 27 Mar 2014)

5. Mantegazza AR, Magalhaes JG, Amigorena S, Marks MS. Presentation of phagocytosed antigens by MHC class I and II.
   
   Traffic
   
   2013; 14(2):135-52.
   
   www.onlinelibrary.wiley.com/doi/10.1111/tra.12026/full
   
   (accessed 28 Mar 2014)

6. Deakin JE, Papenfuss AT, Belov K, Cross JGR, Coggill P, Palmer S, Sims S, Speed TP, Beck S, Graves JAM. Evolution and comparative analysis of the MHC Class III inflammatory region. BMC Genomics2006;7:281.
   
   www.biomedcentral.com/1471-2164/7/281
   
   (accessed 28 Mar 2014)
7. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses.
   
   Annual review of immunology
   
   , 2004; 22: 531-562.
   
   http://www.annualreviews.org/doi/full/10.1146/annurev.immunol.21.120601.141122?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed
   
   (accessed 28 Mar 2014)
8. Kyewski B, Klein L. A central role for central tolerance.
   
   Annual Review of Immunology
   
   2006; 24: 571-606.
   
   www.annualreviews.org/doi/full/10.1146/annurev.immunol.23.021704.115601?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed
   
   (accessed 28 Mar 2014)

9. Ray S, Sonthalia N, Kundu S, Ray SG et al. Autoimmune Disorders: An Overview of Molecular and Cellular Basis in Today’s Perspective.
   
   J Clin Cell Immunol
   
   2012; S10.
   
   www.omicsonline.org/autoimmune-disorders-an-overview-of-molecular-and-cellular-basis-in-todays-perspective-2155-9899.S10-003.pdf
   
   (accessed 29 Mar 2014)

10. Ghodke Y, Joshi K, Chopra A, Patwardhan B. HLA and disease.
    
    European Journal of Epidemiology
    
    2005; 20(6): 475-488. www.link.springer.com/article/10.1007%2Fs10654-005-5081-x (accessed 29 Mar 2014)

11. Möller E. Mechanisms for induction of autoimmunity in humans.
    
    Acta Paediatrica
    
    1998; 87:16-20.
    
    www.onlinelibrary.wiley.com/doi/10.1111/j.1651-2227.1998.tb01228.x/abstract
    
    (accessed 29 Mar 2014)

12. Nepom GT. Class II antigens and disease susceptibility.
    
    Annual Review of Medicine
    
    1995; 46: 17-25.
    
    www.annualreviews.org/doi/full/10.1146/annurev.med.46.1.17?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed
    
    (accessed 31 Mar 2014)

13. Mandelboim O, Wilsons SB, Valés-Gómez M, Reyburn HT, Strominger JL. Self and viral peptides can initiate lysis by autologous natural killer cells. Proc Natl Acad Sci 1997;94(9): 4604–4609.
    
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC20770/
    
    (accessed 31 Mar 2014)
14. McInnes IB, Schett G. The Pathogenesis of Rheumatoid Arthritis.
    
    N Engl J Med
    
    2011; 365:2205-19.
    
    http://www.nedai.org/items/nejmra1004965iainmcinnes.pdf
    
    (accessed 1 Apr 2014)
15. Kallon D. Autoimmune Diseases and HLA.
    
    HLA Disease Associations: The Autoimmune diseases site
    
    [Internet].
    
    www.hladiseaseassociations.com/autoimmune-diseases-and-hla/
    
    (accessed 02 Apr 2014)
16. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.
    
    Arthritis Rheum
    
    1987; 30: 1205-1213. [PubMed: 2446635]

17. Holoshitz J. The rheumatoid arthritis HLA-DBR1 shared epitope.
    
    Curr Opin Rheumatol
    
    2010; 22(3): 293-298.
    
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2921962/
    
    (accessed 02 Apr 2014)
18. de Vries N, Tijssen H, van Riel PLCM, van de Putte LBA. Reshaping the shared epitope hypothesis: HLA-associated risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67–74 of the HLA–DRB1 molecule.
    
    Arthritis & Rheumatism
    
    2002; 46:921–928.
    
    www.onlinelibrary.wiley.com/doi/10.1002/art.10210/abstract
    
    (accessed 03 Apr 2014)

19. National Collaborating Centre for Chronic Conditions (UK). Rheumatoid Arthritis: National Clinical Guideline for Management and Treatment in Adults. London: Royal College of Physicians (UK); 2009. (NICE Clinical Guidelines, No. 79)
    
    www.ncbi.nlm.nih.gov/books/NBK51812/
    
    (accessed 04 Apr 2014)

20. Gillespie KM. Type 1 diabetes: pathogenesis and prevention. CMAJ2006;175(2): 165-170.
    
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1489998/
    
    (accessed 02 Apr 2014)
21. Devendra D, Eisenbarth GS. Immunologic endocrine disorders.
    
    J Allergy Clin Immunol
    
    2003; 111(2): S624-S636.
    
    www.sciencedirect.com/science/article/pii/S0091674902913436#
    
    (accessed 03 Apr 2014)